The human pathobiont <i>Malassezia furfur</i> secreted protease Mfsap1 regulates cell dispersal and exacerbates skin inflammation.

Abstract

<i>Malassezia</i> form the dominant eukaryotic microbial community on the human skin. The <i>Malassezia</i> genus possesses a repertoire of secretory hydrolytic enzymes involved in protein and lipid metabolism which alter the external cutaneous environment. The exact role of most <i>Malassezia</i> secreted enzymes, including those in interaction with the epithelial surface, is not well characterized. In this study, we compared the expression level of secreted proteases, lipases, phospholipases, and sphingomyelinases of <i>Malassezia globosa</i> in healthy subjects and seborrheic dermatitis or atopic dermatitis patients. We observed upregulated gene expression of the previously characterized secretory aspartyl protease <i>MGSAP1</i> in both diseased groups, in lesional and non-lesional skin sites, as compared to healthy subjects. To explore the functional roles of <i>MGSAP1</i> in skin disease, we generated a knockout mutant of the homologous protease <i>MFSAP1</i> in the genetically tractable <i>Malassezia furfur</i>. We observed the loss of <i>MFSAP1</i> resulted in dramatic changes in the cell adhesion and dispersal in both culture and a human 3D reconstituted epidermis model. In a murine model of <i>Malassezia</i> colonization, we further demonstrated Mfsap1 contributes to inflammation as observed by reduced edema and inflammatory cell infiltration with the knockout mutant versus wildtype. Taken together, we show that this dominant secretory <i>Malassezia</i> aspartyl protease has an important role in enabling a planktonic cellular state that can potentially aid in colonization and additionally as a virulence factor in barrier-compromised skin, further highlighting the importance of considering the contextual relevance when evaluating the functions of secreted microbial enzymes.